This invention relates to compounds with {4-aminothiazol-2-ylamino}-benzamide nuclei that demonstrate anti-proliferative activity such as antitumor activity, to processes for preparing these compounds and to pharmaceutical compositions containing such compounds. The invention also relates to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating cancer, viral, microbial, and/or parasitic colonization/infection, as well as other disease states associated with unwanted cellular proliferation, by administering effective amounts of such compounds.
Cell proliferation occurs in response to various stimuli and may stem from deregulation of the cell division cycle (or cell cycle), the process by which cells multiply and divide. Hyperproliferative disease states, including cancer, are characterized by cells rampantly winding through the cell cycle with uncontrolled vigor due to, for example, damage to the genes that directly or indirectly regulate progression through the cycle. Thus, agents that modulate the cell cycle, and thus hyperproliferation, could be used to treat various disease states associated with uncontrolled or unwanted cell proliferation. In addition to cancer chemotherapeutic agents, cell cycle inhibitors are also proposed as antiparasitics (see Gray et al., Curr. Med. Chem., 6, 859-875 (1999)) and recently demonstrated as potential antivirals (see Schang et al., J. Virol., 74, 2107-2120 (2000)). Moreover, the applicability of antiproliferative agents may be expanded to treating cardiovascular maladies such as arteriosclerosis or restenosis (see Braun-Dullaeus et al., Circulation, 98, 82-89 (1998)), and states of inflammation, such as arthritis (see Taniguchi et al., Nature Med., 5, 760-767(1999)) or psoriasis.
Mechanisms of cell proliferation are under active investigation at cellular and molecular levels. At the cellular level, deregulation of signaling pathways, loss of cell cycle controls, unbridled angiogenesis and stimulation of inflammatory pathways are under scrutiny, while at the molecular level, these processes are modulated by various proteins, among which protein kinases are prominent suspects. Overall abatement of proliferation may also result from programmed cell death, or apoptosis, which is also regulated via multiple pathways, some involving proteolytic enzyme proteins.
Among the candidate regulatory proteins, protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxyl group of specific tyrosine, serine or threonine residues in proteins. Typically, such phosphorylation dramatically perturbs the function of the protein, and thus protein kinases are pivotal in the regulation of a wide variety of cellular processes.
Cyclin-dependent kinases (CDKs) are serine-threonine protein kinases that play critical roles in regulating the transitions between different phases of the cell-cycle, such as the progression from a quiescent stage in G1 (the gap between mitosis and the onset of DNA replication for a new round of cell division) to S (the period of active DNA synthesis), or the progression from G2 to M phase, in which active mitosis and cell-division occurs. (See, e.g., the articles compiled in Science, 274, 1643-1677 (1996); and Ann. Rev. Cell Dev. Biol., 13, 261-291 (1997)). CDK complexes are formed through association of a regulatory cyclin subunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e.g., CDK1, CDK2, CDK4, CDK5, and CDK6). As the name implies, the CDKs display an absolute dependence on the cyclin subunit in order to phosphorylate their target substrates, and different kinase/cyclin pairs function to regulate progression through specific phases of the cell-cycle.
Aberrations in this control system, particularly those that affect the function of CDK4 and CDK2, have been implicated in the advancement of cells to the highly proliferative state characteristic of malignancies, particularly familial melanomas, esophageal carcinomas, and pancreatic cancers (see, e.g., Hall et al., Adv. Cancer Res., 68, 67-108 (1996); Kamb, Trends in Genetics, 11, 136-140 (1995); Kamb et al., Science, 264, 436-440 (1994)).
Because CDK4 may serve as a general activator of cell division in most cells and complexes of CDK4/cyclin D and CDK2/cyclin E govern the early G1 phase of the cell cycle, CDK4 or CDK2 inhibitors may be used as anti-proliferative agents. Also, the pivotal roles of cyclin E/CDK2 and cyclin B/CDK1 in the G1/S phase and G2/M transitions, respectively, offer additional targets for therapeutic intervention in suppressing deregulated cell cycle progression.
A large number of small molecule ATP-site antagonists have been identified as CDK inhibitors (see, Webster, Exp. Opin. Invest. Drugs, 7, 865-887 (1998); Stover et al., Curr. Opin. Drug Disc. Dev., 2, 274-285(1999); Gray et al., Curr. Med. Chem., 6, 859-875 (1999); Sielecki et al., J. Med. Chem., 43, 1-18 (2000); Crews et al., Curr. Opin. Chem. Biol., 4, 47-53 (2000); Buolamwini, Curr. Pharm. Des., 6, 379-392 (2000); and Rosania et al., Exp. Opin. Ther. Pat., 10, 215-230 (2000)).
In addition to the protein kinases identified above, many other protein kinases have been considered to be therapeutic targets, and numerous publications disclose inhibitors of kinase activity, as reviewed in the following: McMahon et al., Curr. Opin. Drug Disc. Dev., 1, 131-146 (1998); Strawn et al., Exp. Opin. Invest Drugs, 7, 553-573 (1998); Adams et al., Curr. Opin. Drug Disc. Dev., 2, 96-109 (1999); Stover et al., Curr. Opin. Drug Disc. Dev., 2, 274-285 (1999); Toledo et al., Curr. Med Chem., 6, 775-805 (1999); and Garcia-Echeverria et al., Med. Res. Rev., 20, 28-57 (2000).
Among others, the following patent publications disclose thiazole compounds: International Publication No. WO 99/21845 discloses certain 2,4-diaminothiazoles as CDK inhibitors; International Publication No. WO 99/62890 discloses certain isothiazoles as anticancer agents; International Publication No. WO 98/04536 describes certain thiazoles as protein kinase C inhibitors; and European Publication No. EP 816362A(1998) discloses certain thiazoles useful as dopamine D4 receptor antagonists. Certain aminothiazoles are reported in International Publication No. WO 99/65844 and International Publication No. WO 99/24416, and certain aminobenzothiazoles are disclosed in International Publication No. WO 99/24035. International Publication No. WO 00/17175 describes certain other aminothiazoles as p38 mitogen-activated protein (MAP) kinase inhibitors, and International Publication No. WO 00/26202, International Publication No. WO 00/26203, and U.S. Pat. No. 6,114,365 describe certain aminothiazoles and certain ureidothiazoles as anti-tumor agents. International Publication No. WO 99/21845 discloses certain 4-aminothiazole derivatives containing unsubstituted nitrogen or primary benzamides.
There is still a need, however, for more potent inhibitors of protein kinases. Moreover, as is understood by those skilled in the art, it is desirable for kinase inhibitors to possess both high affinity for the target kinase as well as high selectivity versus other protein kinases.
An object of the invention is to discover potent anti-proliferative agents. Another object of the invention is to discover effective inhibitors of protein kinases.
These and other objects of the invention, which will become apparent from the following description, have been achieved through the discovery of 4-aminothiazole compounds with mono- or di-N-substituted benzamides. The invention also relates to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds (such compounds, prodrugs, metabolites and salts are collectively referred to as xe2x80x9cagentsxe2x80x9d) which modulate and/or inhibit cell growth.
Thus, the inventive agents and pharmaceutical compositions containing such agents are useful in treating various diseases or disorder states associated with uncontrolled or unwanted cellular proliferation, such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders, and cardiovascular diseases.
Further, the agents modulate and/or inhibit the activity of protein kinases, for example one or more CDKs, such as CDCK1, CDK2, CDK4 and/or CDK6, or cyclin complexes thereof, and/or one or more LCKs, VEGF or FGFs. Thus, the pharmaceutical compositions containing such agents are useful in treating diseases mediated by kinase activity, such as cancer.
In a general aspect, the invention relates to compounds represented by Formula (I): 
wherein:
R1 and R2 are each independently hydrogen, or an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amino alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRc, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94COxe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above, where R1 and R2 are not both hydrogen, or
R1 or R2, together with the 
and two adjacent carbon atoms of the phenyl ring of Formula (I), forms a 5- or 6-membered ring structure fused to the phenyl ring of Formula (I) and unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, xe2x80x94Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94COxe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above; or
R1 and R2, taken together with the nitrogen atom to which they are bonded, form a monocyclic or fused or non-fused polycyclic structure which may contain one to three additional heteroatoms, unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94COxe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, xe2x80x94NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, xe2x80x94Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94CO-NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above;
R3 is an aryl, heteroaryl, alkyl, or cycloalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, xe2x80x94Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94COxe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, xe2x80x94NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above; and
Y is hydrogen, alkyl, heteroalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, cycloalkyl, heterocycloalkyl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94CO2xe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl.
The nitrogen-containing ring optionally formed by R1 and R2 may be monocyclic, or fused or un-fused polycyclic (i.e. spiral), and may contain one to three additional heteroatoms selected from N, O or S. Examples of such a ring include 
and the like. The ring may be substituted with one or more substituents as described above.
According to one preferred embodiment of the invention, (C(O)N(R1)(R2)) moiety is connected meta or para to the secondary amine linking the phenyl and thiazole rings, and Y can be at any position on the phenyl ring. More preferably, the (C(O)N(R1)(R2)) moiety is para and Y is meta to the secondary amine linking the phenyl and thiazole rings. 
In one preferred embodiment of the invention, in the compounds of Formula (I), R3 is an aryl or heteroaryl group having one or more substituents selected from the group consisting of a halogen, alkoxy, xe2x80x94OH, alkyl and xe2x80x94NO2 groups.
The invention is also directed to pharmaceutically acceptable salts of compounds represented by the Formula (I), pharmaceutically acceptable prodrugs, pharmaceutically active metabolites of compounds represented by the Formula (I), and pharmaceutically acceptable salts of such metabolites. Advantageous methods of making the compounds of the Formula (I) are also described.
In a preferred general embodiment, the invention relates to compounds represented by Formula (II): 
wherein:
R1 is selected from the group consisting of: alkyl, alyenyl, alkynyl, heteroalkyl, halogen, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94CO2xe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above; and
R4, R5, and R6 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94CO2xe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Re, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above.
Preferred compounds of the invention include those represented by Formula (II) wherein R1 is an alkyl, heteroalkyl or heterocycloalkyl group substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94CO2xe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, -NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above. Preferably, the substituted alkyl for R1 is xe2x80x94N(R7)(R8) where R7 and R8 are each independently an alkyl, alkyl-(heterocycloalkyl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94COxe2x80x94ORe, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above, or alkyl-(substituted aryl) group unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, xe2x80x94OH, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94ORb, xe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94Oxe2x80x94ORc, keto (xe2x95x90O), thioketo (xe2x95x90S), xe2x80x94SO2xe2x80x94Rc, xe2x80x94SOxe2x80x94Rc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94NRcxe2x80x94COxe2x80x94Re, xe2x80x94NRcxe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94SO2xe2x80x94Rc, xe2x80x94Oxe2x80x94SOxe2x80x94Rc, xe2x80x94Oxe2x80x94Sxe2x80x94Rc, xe2x80x94Sxe2x80x94COxe2x80x94Rc, xe2x80x94SOxe2x80x94COxe2x80x94ORc, xe2x80x94SO2xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94SO3, xe2x80x94NRcxe2x80x94SRd, xe2x80x94NRcxe2x80x94SOxe2x80x94Rd, NRcxe2x80x94SO2xe2x80x94Rd, xe2x80x94COxe2x80x94SRc, xe2x80x94COxe2x80x94SOxe2x80x94Rc, xe2x80x94COxe2x80x94SO2xe2x80x94Rc, xe2x80x94CSxe2x80x94Rc, xe2x80x94CSOxe2x80x94Rc, xe2x80x94CSO2xe2x80x94Rc, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94Oxe2x80x94CSxe2x80x94Rc, xe2x80x94Oxe2x80x94CSOxe2x80x94Rc, xe2x80x94Oxe2x80x94CSO2xe2x80x94Rc, xe2x80x94SO2xe2x80x94NRdRe, xe2x80x94SOxe2x80x94NRdRe, xe2x80x94Sxe2x80x94NRdRe, xe2x80x94NRdxe2x80x94CSO2xe2x80x94Rd, xe2x80x94NRcxe2x80x94CSOxe2x80x94Rd, xe2x80x94NRcxe2x80x94CSxe2x80x94Rd, xe2x80x94SH, xe2x80x94Sxe2x80x94Rb, and xe2x80x94PO2xe2x80x94ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, xe2x80x94COxe2x80x94Rc, xe2x80x94COxe2x80x94ORc, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94COxe2x80x94NRdRe, xe2x80x94OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, xe2x80x94CORf, xe2x80x94COORf, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rf, xe2x80x94Oxe2x80x94COxe2x80x94Rf, xe2x80x94OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is 0-4, halogen, haloalkyl, haloaryl, xe2x80x94OH, keto (xe2x95x90O), xe2x80x94Nxe2x80x94OH, Nxe2x80x94ORc, xe2x80x94NRdRe, xe2x80x94COxe2x80x94NRdRe, xe2x80x94COxe2x80x94ORc, xe2x80x94COxe2x80x94Rc, xe2x80x94NRcxe2x80x94COxe2x80x94NRdRe, xe2x80x94Cxe2x80x94COxe2x80x94ORc, xe2x80x94NRcxe2x80x94COxe2x80x94Rd, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rc, xe2x80x94Oxe2x80x94COxe2x80x94NRdRe, xe2x80x94SH, xe2x80x94Oxe2x80x94Rb, xe2x80x94Oxe2x80x94Raxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above; and
R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, xe2x80x94OH, C1-C3-alkoxy, C1-C3-alkyl, heteroalkyl, or xe2x80x94Nxe2x80x94CORc, xe2x80x94SRc, xe2x80x94Sxe2x80x94Rb, xe2x80x94SO2Rc, and xe2x80x94COxe2x80x94Rc, where Rc is as defined above.
The invention also relates to methods of treating proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular diseases, comprising administering effective amounts of a compound of Formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite to a subject in need of such treatment.
The invention further relates to a method of modulating and/or inhibiting the kinase activity of one or more CDKs such as CDK1, CDK2, CDK4, and/or CDK6 or cyclin complexes thereof, VEGF, FGF and/or LCK by administering a compound of Formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable salt of such compound or metabolite thereof.
The invention also relates to pharmaceutical compositions, each comprising an effective amount of an agent selected from compounds of Formula (I) and pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable salts of such compounds and metabolites, and a pharmaceutically acceptable carrier or vehicle for such agent.
The inventive compounds of Formula (I) are potent anti-proliferative agents. The compounds are also useful for mediating the activity of protein kinases. More particularly, the compounds are useful as agents for modulating and/or inhibiting the activity of various enzymes, for example protein kinases, thus providing treatments for cancer or other diseases associated with uncontrolled or abnormal cellular proliferation.
The diseases or disorders in association with uncontrolled or abnormal cellular proliferation include the following:
a variety of cancers, including carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi""s sarcoma and the like.
a disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
defective apoptosis-associated conditions, such as cancers (including those types mentioned hereinabove), viral infections (including herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including Alzheimer""s disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson""s disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including osteroporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.
The agents of the invention may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.
Moreover, the agents of the invention, as inhibitors of CDKs, can modulate the level of cellular RNA and DNA synthesis and therefore are useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.
The terms xe2x80x9ccomprisingxe2x80x9d and xe2x80x9cincludingxe2x80x9d are used herein in their open, non-limiting sense.
The term xe2x80x9calkylxe2x80x9d as used herein refers to straight- and branched-chain alkyl groups having from one to twelve carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.
The term xe2x80x9cheteroalkylxe2x80x9d as used herein refers to straight- and branched-chain alkyl groups having from one to twelve atoms containing one or more heteroatoms selected from S, O, and N.
The term xe2x80x9calkenylxe2x80x9d refers to straight- and branched-chain alkenyl groups having from two to twelve carbon atoms. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.
The term xe2x80x9calkynylxe2x80x9d refers to straight- and branched-chain alkynyl groups having from two to twelve carbon atoms. Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like.
The term xe2x80x9carylxe2x80x9d (Ar) refers to monocyclic and polycyclic aromatic ring structures containing only carbon and hydrogen. Illustrative examples of aryl groups include the following moieties: 
The term xe2x80x9cheteroarylxe2x80x9d (heteroAr) refers to monocyclic, or fused polycyclic aromatic ring structures which include one or more heteroatoms selected from nitrogen, oxygen and sulfur and having from 3 to 12 ring atoms per ring. The polycyclic heteroaryl group may be fused or non-fused. More preferably, illustrative examples of heteroaryl groups have from 4 to 7 ring atoms per ring, such as the following moieties: 
The term xe2x80x9ccycloalkylxe2x80x9d refers to saturated carbocycles having from three to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl structures. Illustrative examples of cycloalkyl groups include the following moieties: 
A xe2x80x9cheterocycloalkylxe2x80x9d group refers to a monocyclic or fused or spiro polycyclic ring structure radical which may be saturated or unsaturated and contains from three to twelve ring atoms, selected from carbon and heteroatoms, preferably 4 or 5 ring carbon atoms, and at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. More preferably, illustrative examples of heterocycloalkyl groups have 4 to 7 ring atoms per ring, such as the following moieties, 
The term xe2x80x9calkoxyxe2x80x9d refers to the radical xe2x80x94Oxe2x80x94R where R is an alkyl as defined above. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and the like.
The term xe2x80x9chalogenxe2x80x9d represents chlorine, fluorine, bromine or iodine. The term xe2x80x9chaloxe2x80x9d represents chloro, fluoro, bromo or iodo.
The term xe2x80x9calcoholxe2x80x9d refers to the radical xe2x80x94Rxe2x80x94OH where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or cycloalkyl as defined above. Examples of alcohols include methanol, ethanol, propanol, phenol and the like.
The term xe2x80x9cacylxe2x80x9d represents xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94OC(O)R or xe2x80x94OC(O)OR where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or cycloalkyl as defined as above.
The term xe2x80x9camidexe2x80x9d refers to the radical xe2x80x94C(O)N(Rxe2x80x2)(Rxe2x80x3) where Rxe2x80x2 and Rxe2x80x3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, xe2x80x94OH, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl as defined above; or Rxe2x80x2 and Rxe2x80x3 cyclize together with the nitrogen to form a heterocycloalkyl or heteroaryl as defined above.
The term xe2x80x9csubstitutedxe2x80x9d as used herein means that the group in question, e.g., alkyl group, etc., may bear one or more substituents.
The alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups and the substituents containing these groups, as defined hereinabove, may be optionally substituted by at least one other substituent. The term xe2x80x9coptionally substitutedxe2x80x9d is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more substituents from the list above. Various groups may be unsubstituted or substituted (i.e., they are optionally substituted) as indicated.
If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley and Sons, NY (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.
Some of the inventive compounds may exist in various stereoisomeric or tautomeric forms. The present invention encompasses all such cell proliferation-inhibiting compounds, including active compounds in the form of single pure enantiomers (i.e., essentially free of other stereoisomers), racemates, mixtures of enantiomers and/or diastereomers, and/or tautomers. Preferably, the inventive compounds that are optically active are used in optically pure form.
As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess (xe2x80x9ce.e.xe2x80x9d) or diastereomeric excess (xe2x80x9cd.e.xe2x80x9d)), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
Additionally, the formulae are intended to cover solvated as well as unsolvated forms of the identified structures. For example, Formula I includes compounds of the indicated structure in both hydrated and non-hydrated forms. Additional examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In addition to compounds of Formula I, the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means pharmacologically acceptable and substantially non-toxic to the subject being administered the agent.
xe2x80x9cA pharmaceutically acceptable prodrugxe2x80x9d is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound. xe2x80x9cA pharmaceutically active metabolitexe2x80x9d is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
xe2x80x9cA pharmaceutically acceptable saltxe2x80x9d is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Pharmaceutical compositions according to the invention may, alternatively or in addition to a compound of Formula I, comprise as an active ingredient pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites. Such compounds, prodrugs, multimers, salts, and metabolites are sometimes referred to herein collectively as xe2x80x9cactive agentsxe2x80x9d or xe2x80x9cagents.xe2x80x9d
In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
Therapeutically effective amounts of the active agents of the invention may be used to treat diseases mediated by modulation or regulation of protein kinases. An xe2x80x9ceffective amountxe2x80x9d is intended to mean that amount of an agent that significantly inhibits proliferation and/or prevents de-differentiation of a eukaryotic cell, e.g., a mammalian, insect, plant or fungal cell, and is effective for the indicated utility, e.g., specific therapeutic treatment.
The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. xe2x80x9cTreatingxe2x80x9d is intended to mean at least the mitigation of a disease condition in a subject such as mammal (e.g., human), that is affected, at least in part, by the activity of one or more kinases, for example protein kinases such as tyrosine kinases, and includes: preventing the disease condition from occurring in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition.
Agents that potently regulate, modulate, or inhibit cell proliferation are preferred. For certain mechanisms, inhibition of the protein kinase activity associated with CDK complexes, among others, and those which inhibit angiogenesis and/or inflammation are preferred. The present invention is further directed to methods of modulating or inhibiting protein kinase activity, for example in mammalian tissue, by administering an inventive agent. The activity of agents as anti-proliferatives is easily measured by known methods, for example by using whole cell cultures in an MTT assay. The activity of the inventive agents as modulators of protein kinase activity, such as the activity of kinases, may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays. Examples of suitable assays for activity measurements include those described in International Publication No. WO 99/21845; Parast et al., Biochemistry, 37, 16788-16801 (1998); Connell-Crowley and Harpes, Cell Cycle: Materials and Methods, (Michele Pagano, ed. Springer, Berlin, Germany)(1995); International Publication No. WO 97/34876; and International Publication No. WO 96/14843. These properties may be assessed, for example, by using one or more of the biological testing procedures set out in the examples below.
The active agents of the invention may be formulated into pharmaceutical compositions as described below. Pharmaceutical compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Formula I or Formula II and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving anti-proliferative ability. By xe2x80x9cefficacious levelsxe2x80x9d is meant levels in which proliferation is inhibited, or controlled. These compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.
An inventive agent can be administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an inventive agent can be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. Administration of prodrugs is typically dosed at weight levels which are chemically equivalent to the weight levels of the fully active form.
The compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically.
Proper formulation is dependent upon the route of administration chosen. For injection, the gents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks""s solution, Ringer""s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of agents.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the agents in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions take the form of tablets or lozenges formulated in conventional manners.
For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the agents in water-soluble form. Additionally, suspensions of the agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
For administration to the eye, the agent is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous and aqueous humor.
Alternatively, the agents may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described above, the agents may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
An exemplary pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
The agents of the invention may be useful in combination with known anti-cancer treatments such as: DNA interactive agents such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents such as paclitaxel, docetaxel or the epothilones; hormonal agents such as tamoxifen; thymidilate synthase inhibitors such as 5-fluorouracil; and anti-metalbolites such as methotrexate. They may be administered together or sequentially, and when administered sequentially, the agents may be administered either prior to or after administration of the known anticancer or cytotoxic agent
The agents may be prepared using the reaction routes and synthesis schemes as described below, employing the general techniques known in the art using starting materials that are readily available. The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other anti-proliferatives or protein kinase inhibitors of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or generally known in the art will be recognized as having applicability for preparing other compounds of the invention.